Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation

Abstract

Keeping RNA processing contained Biomolecular condensates that assemble by phase separation are involved in RNA processing. Posttranslational modifications in intrinsically disordered regions of proteins can regulate RNA processing by regulating phase separation. Kim et al. used nuclear magnetic resonance spectroscopy to characterize phase separation in a model system comprising the C-terminal disordered regions of the translational regulators FMRP and CAPRIN1 that repress translation by deadenylating mRNA. Interactions between the proteins involve specific sequences in FMRP and CAPRIN1, and the propensity for mRNA to partition into the condensates depends on the phosphorylation patterns in the disordered regions. This mechanism integrates signaling pathways with the regulation of RNA processing. Science, this issue p. 825 Residue-specific interactions within protein-RNA condensates enable phosphoregulation of RNA processing and translation. Membraneless organelles involved in RNA processing are biomolecular condensates assembled by phase separation. Despite the important role of intrinsically disordered protein regions (IDRs), the specific interactions underlying IDR phase separation and its functional consequences remain elusive. To address these questions, we used minimal condensates formed from the C-terminal disordered regions of two interacting translational regulators, FMRP and CAPRIN1. Nuclear magnetic resonance spectroscopy of FMRP-CAPRIN1 condensates revealed interactions involving arginine-rich and aromatic-rich regions. We found that different FMRP serine/threonine and CAPRIN1 tyrosine phosphorylation patterns control phase separation propensity with RNA, including subcompartmentalization, and tune deadenylation and translation rates in vitro. The resulting evidence for residue-specific interactions underlying co–phase separation, phosphorylation-modulated condensate architecture, and enzymatic activity within condensates has implications for how the integration of signaling pathways controls RNA processing and translation.